1-(3-(AMINO ALKYL)-2-OXO-2H-1-benzopyran-7-yl)-ureas

ABSTRACT

Compounds having the general formula (I)   and salts thereof with physiologically acceptable acids, in which R1, R2, R5 and R6 represent hydrogen atoms, straight-chain or branched-chain alkyl groups with up to 4 carbon atoms, cycloalkyl, aralkyl, aryl groups or the radicals R1 and R2, and/or radicals R5 and R6, when taken together with the adjacent nitrogen atom represent heterocyclic compounds with 3 to 7 ring members of which 1 to 3 can be hetero atoms, providing that R1, R2 and R5 and R6 can be the same or different radicals, and also the groups -NR1R2 and -NR5R6 can be the same or different, R4 represents a hydrogen atom or a lower alkyl group with up to 3 carbon atoms, R7 represents a hydrogen atom, a lower alkyl group with up to 3 carbon atoms or an aryl group, Z represents a halogen atom, a lower alkyl or alkoxy group with up to 3 carbon atoms, N REPRESENTS A NUMBER FROM 0 TO 2, AND U represents a straight-chain or branched-chain lower alkylene group with 2 to 5 carbon atoms in which a hydrogen atom can be replaced by a hydroxyl group. These compounds have utility as coronary dilatators.

United States Patent [191 Becker et al.

[ July 29, 1975 [73] Assignee: Troponwerke Dinklage & Company, Cologne, Germany [22] Filed: July 15, 1972 [21] Appl. No.: 163,110

[30] Foreign Application Priority Data July 17, 1970 Germany 2035536 Feb. 20, 1971 Germany 2108185 52] us. Cl....260/246 B; 260/2472 A; 260/2472 B; 260/268 BC; 260/293.58; 260/326.25;

51 int. Cl C07d 87/42 [58] Field of Search 260/3432 R, 246 B, 293.58, 260/268 BC, 247.2 A, 247.2 B, 326.25, 326.34

[56] References Cited UNITED STATES PATENTS 2,88l,l86 4/1959 Hewsermann 260/3432 R23,703 9/1953 Ackermann 260/3432 OTHER PUBLICATIONS L. Reppel et al., Chemical Abstracts, Vol. 65, p. 677, 1966).

Primary ExaminerDonald G. Daus Assistant Examiner-.lose Tovar Attorney, Agent, or Firm-Burgess, Dinklage & Sprung 57 7 ABSTRACT Compounds having the general formula (I) R (2),, .5 9 o R6-N-C-N N R Ru U 2 and salts thereof with physiologically acceptable acids, in which R R R and R represent hydrogen atoms, straight-chain or branched-chain alkyl groups with up to 4 carbon atoms, cycloalkyl, aralkyl, aryl groups or the radicals R and R and/or radicals R and R when taken together with the adjacent nitrogen atom represent heterocyclic compounds with 3 to 7 ring members of which 1 to 3 can be hetero atoms, providing that R R and R and R can be the same or dif ferent radicals, and also the groups -NR R and NR R can be. the same or different,

R. represents a hydrogen atom or a lower alkyl group with up to 3 carbon atoms, R represents a hydrogen atom, a lower alkyl group with up to 3 carbon atoms or an aryl group, Z represents ahalogen atom, a lower alkyl or alkoxy group with up to 3 carbon atoms, n represents a number from 0 to 2, and U represents a straight-chain or branched-chain lower alkylene group with 2 to 5 carbon atoms in which a hydrogen atom can be replaced by a hydroxyl group.

These compounds have utility as coronary dilatators.

20 Claims, No Drawings v l-(3-(AMINO ALKYL)-2-0X0-2H-l-BENZOPYRAN-7-YL)- UREAS This invention relates to novel coumarine derivatives 5 having utility as coronary dilatators.

The invention provides coumarine derivatives effective as coronary dilatators of the general formula (I) R (Z011 R i1 5 N 0 5 l fil R4 U- N n and salts thereof with physiologically acceptable acids, in which R R R and R represent hydrogen atoms, straightchain or branched-chain alkyl groups with up to 4 carbon atoms, in which a hydrogen atom may be replaced by a hydroxyl group, cycloalkyl, aralkyl or aryl groups advantageously with a single ring system and hence up to a maximum of 8 carbon atoms in the respective radical, which optionally can be substituted by l or 2 halogen atoms, lower alkyl groups (preferably C, to C lower alkoxy groups (preferably C to C alkoxy), hydroxyl groups or trifluoromethyl groups, and in which the radicals R and R as well as R and R may together with the adjacent nitrogen atom, represent heterocyclic compounds with 3 to 7 ring members, of which 1 to 3 can be hetero atoms, the heterocyclic compounds being if desired substituted with one or two substituents such as aryl (preferably with 1 ring system) or lower (preferably C, to C alkyl groups or lower (preferably C to C alkyl groups substituted by a hydroxyl group, halogen atoms or trifluoromethyl groups, while these radicals R R R and R can be like or different radicals and in addition also the pairs -NR R or -NR R can be like or different,

R represents a hydrogen atom or a lower alkyl group with up to 3 carbon atoms,

R represents a hydrogen atom, a lower alkyl group with up to 3 carbon atoms or an aryl group with advantageously 1 ring system,

Z represents a halogen atom or a lower'alkyl or alkoxy group with up to 3 carbon atoms,

n represents the numbers from 0 to 2, and

U represents a straight-chain or branched-chain lower alkylene group with 2 to 5 carbon atoms in which one hydrogen atom can be replaced by a hydroxyl group.

The invention also provides a process for the preparation of compounds of the general formula I, in which R to R U, Z and n are as defined above, which comprises reacting together a, Compounds of the general formula (ll) 0 0 ll Rs- 0- c N o 4 U- N R2 7 in which R R R R U, Z and n have the meanings indicated, and R stands for an alkyl or aryl group, or compounds of the general formula (III) U-Hal (III) in which R R R U, Z and n have the meaning indicated and Hal represents a halogen atom,

or compounds of the general formula (IV) different therefrom,

or compounds of the general formula (V) in which R,, R R-,, U, Z and n have the meaning indicated,

or compounds of the general formula (VI) in which R,, R R R U, Z and n have the meaning indicated and Hal stands for a halogen atom;

with compounds of the general formula (Vll) l HN-R H (VII) in which R, and R or R and R.,, respectively, have the meaning indicated above, but in the case of the reaction of compounds of the general formula IV, the radical -NR R is not identical to the radical of the secondary amine of the general formula (VII).

The compounds of the invention may also be prepared by reacting compounds of the general formula (VIII) R, NH (V111) f1 U N R2 in which R and R have the meaning indicated,

or with compounds of the general formula (XI) followed by subsequent saponification of the initially forming =NI-I group in which R and R have the meaning indicated.

The reaction of compounds of the general formula II with compounds of the general formula VII is especially suitable for the preparation of compounds of the general formula I, in which R, and R are different from R and R This reaction is effected by simply heating the components in the absence of a solvent; however, it is preferred to carry out the reaction in the presence of a solvent. Polar solvents such as dimethyl formamide and dimethyl sulphoxide have proved satisfactory, but chloroform, ethylene chloride, chlorobenzene, and nitrobenzene are preferred because of their better solution properties. Inert, aromatic hydrocarbons, such as benzene and toluene, are found to be less suitable.

The reaction takes place is particularly smooth when using compounds of formula II, in which R represents an aryl group, especially when R is a phenyl group. In this case, the reaction can be carried out by simply stirring at room temperature and good yields are obtained.

However, if R represents a lower alkyl group, for example an ethyl group, the reaction is preferably effected with heating advantageously at temperatures between 50 and 120C.

For preparing compounds of the general formula I, in which R and R have the same meaning as R; and R the compounds of the general formula III are preferably used as initial material. The reaction takes place by sample heating in the excess of compounds of the general formula VII, in the presence or absence of a solvent. In preparing these compounds, inert solvents in addition to those mentioned above, with the exception of dimethyl formamide, have also been found to be satisfactory.

Particularly significance is attributed to the preparation of compounds of the general formula I by the reamidation of compou'nds of the general formula IV. Consequently, this reaction is particularly preferred. A basis for this process is the discovery that in the compounds of formula I, the group NR R and thus the group NR R, is the compounds formula IV, are exchangeable, but the group -"NR' R is'not exchangeable, under the same conditions. The group NR R in the compounds of formula IV can hence be transformed by a simple-re-amidation with the amines of formula VII into the required group. The re-amidation leads to almost quantitative yields, if the amine of formula VII which is to be used is less volatile than the amine HNR R to be split off. In this case, the latter can be constantly removed by distillation from the reaction mixture and the reaction can be conducted until the exchange is complete. However, the reaction equilibrium can be displaced to the required side simply with an excess of the amine of formula VII. This is particularly simple, for example, when the amine VII can be used as liquid solvent for IV.

For preparing compounds of the general formula I, in which R represents an alkyl group, the processes so far fully explained are less suitable for use, since the reactions proceed less readily and require more forcing conditions, which lead to side products and thus to a reduction in the yield. In these cases, it is preferred to use the compounds of the general formulae VI and VIII as initial products, the compounds of the formula VI merely representing the reaction products of compounds of formula VIII with phosgene, which advantageously is not isolated, but is immediately reacted with compounds of the formula VII.

One particularly intersecting and accordingly important compound of the invention is the new pharmacologically active compound N-[3-(2-morpholinoethyl)- 4-methyl-2-oxo-2l-I-l-benzopyran-7-yl]-4-morpholine carboxamide as well as the salts thereof formed with physiologically compatible acids.

The compounds la has a strong coronary-dilating efficiency, such as shown by tests on the basis of pharma-' cological test specimens. With intravenous application of 1 mg/kg of body weight to the narcotised dog, the coronary flow is increased by 2 to 5 times, the effect lasting more than one hour. At the same time, the arteriovenous oxygen difference (AVD) as a typical.

sign of an increased supply of oxygen to the heart muscle is correspondingly reduced. By contrast with the chemically related compound u-[3 -(2- diethylaminoethyl )-4-methyl--2-oxo-2H- l -benzopyran- 7-yl]oxyeacetic acid ethyl ester, (I.N.N. carboeromene; referred to hereinafter as CBC), which has been used therapeutically as a coronary dilatator in human medicine for years, Ia leads to a strong and long-lasting improvement in the coronary blood flow and to a reduction of the AVD, by both intravenous or enteral application. Whereas doses of 20 mg/kg of body weight with enteral administration of CBC to the narcotised dog remained without any effect on the coronary flow (see also D. LORENZ and H.D. DELL, Tenth Spring Conference of the German Pharmacological Associa- CH -CI-l2-Ha1 tion from the 16th to 19th March 1969, special print from Naunyn-Schmiedebergs Archiv fi'ir Pharmakolo- H III? gie, 264 (1969), Issue No. 3, pages 272-273, and also u D LENKE in Arzneimittelforschung 20 p g m which R represents a lower alkyl radical, preferably 655), la resulted in a strong increase in the coronary h up to 5 (farbon atoms or an aryl or aralkyl radical blood flow in a dose range from to 20 mg/kg on the 10 prefrably with up to 10 carbon atoms Hal Fepre' same test animal and with the same method of adminis- 7 atom preferilbly m whlch Cl tration, this increase corresponding in its degree to that p i at y g i fi. wlth morpholme and .thus according to intravenous administration, but also lasti c-onipoun a w be.convened wlth a g Substantially longerp yslo o g ca ly acceptable acid into its salt.

The initial compounds of the general formula llla are referabl re ared b condensation, for exam le, in The descr bed effect of la on the coronary flow from fi g i z megium of compounds of gem enteral application is due to the fact that la 1S resorbed eral formula I from the intestinal tract and shows a substantially greater stability in the organism as compared with 9 CBC. Whereas after enteral administration of CBC in NH-C-OR doses of 20 mg/kg, small quantities of unchanged CBC could be detected in the blood of the test animals only a few minutes after the application (amounts of 0.002 0.04 y per 5 ml of blood were found), with doses ap- OH plied Orally to the nonmarcotised dog of 20 mg/kg of in which R has the meaning rndicated above, with la, amounts of 13] 69 7 per 5 m] of blood of 3-acetyl-2-oxotetrahydrofuran. In this case, comchanged Ia have been detected minutes after applipounds of the general formula cation, and even after 4 hours, it was still possible to de- 0 tect half of the concentration found after 30 minutes. 0 From the comparison of the concentration of la in the 30 blood after intravenous and oral application, there is 3 obtained a resorbtion quota of 30 50% of the orally 2 2 administered la. CH3

are initially formed, The substantiall reater stabilit of la in blOlO lcal medium as compai ei to CBC was proved with in itro 2112 si i g z gg zig ggl $22 33? :3 }?22t ::f ggi l sss i 3 2 52 3 23 quently halogenated by the corresponding halogena- 100% of the quantity used were degraded after 10 min- 40 z zgrz Ounds of the eneral formula I wh utes, the total quantity of la could be detected without plied intravgnously in a doiage of 1 2 g ils;- change after incubation lasting up to 8 hours. The rapid ht t th d d h t g degradation of CBC is due to the enzymatic cleavage 3525 g i z gi i iz i figfi z by esterases, as already described by M. KLARWElN Tabli 2 Shows {h following data and R. E. NlTZ in Arzneimittelforschung 15, page 555 Column 1, The Structures of compounds being (1965). la is stable with respect to this enzyme group investigated; tgzcrziastssmofl213352332235:gig-1d: acllsiglzrlipgreiatrhsetgi e- I c l g n iebTicli wa nfizies of substances administered quite Stable in relation to other enzyme .systems as 35111511 3; in: ch a i ige in the arterial blood pressure g gzl g g zgg glfz g fg rfi f l s i g j gg g in the left ventricle (if there are two symbols, the first as unmodified Ia Within 3 days. represents the change in the systolic blood pressure and the second the change in the diastolic blood pressure); Column 4: The change in the blood flow from the The invention is also concerned with a process for coronary sinus; preparing N-[3-(Z-morpholinoethyl)4-methyl-2-oxo- Column 5: The change in the oxygen saturation of 2H-l-benzopyran-7-yl]-4-morpholine carboxamide the coronary sinus blood; (la) and its salts formed with physiologically accept- Column 6: The change in the heart frequency. able acids, which comprises reacting compounds of the The meaning of the symbols used in Table 2 is exgeneral formula plained in Table 1:

TABLE 1 Column 3 Column 4 Column 5 Column 6 Increase/decrease Blood Blood flow 02-satur. Heart frepressure coronary in quency in mm. Hg sinus in% beats/min.

d: 4: up to 10 up to 10 up to 10 up to 10 (+1 up to 20 up to 20 up to 20 up to 20 up to 50 up to 50 up to 30 up to 50 -H- up to 100 up to I00 up to 50 up to 4-H- above above 100 above 50 above 80 Table 2 Continued Table 3 shows test values obtained on a narcotised cance as those of Table 2 and the symbols used are exdog after intraduodenal administration of the sub- 40 plained in Table l. stances. The columns of Table 3 have the same signifi Table 3 It is apparent that compounds of the invention have a strong coronary-dilating efficiency even when administered enterally, the duration of the effect being from 1 to 3 hours.

From 4 to narcotised dogs were used for each investigation. The investigations as regards circulation were carried out in accordance with standard methods further developed by the applicants and explained below.

In the investigation of circulation on a narcotised dog 7 with a closed thorax mongrel dogs and weighing from to 30 kg were narcotised, after premedication by morphine (2 mg/kg s.c.), with a mixture of ethylurea, urethane and diallyl-barbituric acid (120: l 20:30 mg/kg i.v.) and given artificial respiration with a narcosis apparatus of Messrs. Drager.

For measuring the coronary sinus flow, a catheter with electromagnetic flow head according to LOCHNER and OSWALD was introduced under x-ray control into the sinus coronarius.

The peripheral through flow was measured in the A. femoralis. For both flow measurements an electromag netic flow meter of Messrs. Statham was used.

The oxygen content in the arterial and sinus blood was calibrated with the OSM l of Messrs. Radiometer and recorded during the duration of the experiment with the relative oxymeter of Messrs. Hellige.

The pressure in the left ventricle was recorded with a catheter according to Pieper via pressure-measuring bridges of Messrs. Hellige, the pressure in the A. abdominalis and the pressure in the right auricle were recorded with Statham elements of Messrs. Hellige via pressure-measuring bridges.

The CO content in the expiration air was measured with an Uras M of Messrs. Hartmann and Brown. For the application of the intraduodenal substance, the abdomen was opened and a probe introduced through the stomach into the duodenum.

The new compounds of the invention may be administered in the usual ways, in particular, orally and/or intravenously. The invention correspondingly covers pharmacological preparations or medicines which contain the active principles of the invention. Normally, they are prepared together with usual carrier substances in solid or liquid form.

In the case of oral administration, tablets or dragees are particularly suitable. The active content of such forms is, for example, between 100and 300 mg per tablet or dragee. With solutions for injection, the content of active principle for one administration is, for example, between 50 and 150 mg.

Examples of suitable compositions of substances for some of the most important forms of administration are found at the end of the examples concerned with the preparation of the new compounds.

The following Examples illustrate the invention:

EXAMPLE 1 N-l3-[2-(4-phenylpiperazin-1-yl)ethyl]-4-methyl-2- oxo-2H- l -benzopyran-7-yl}-4-phenyl-l -piperazine carbonxamide.

9.29 g (0.03 mol) of ethyl N-[3-(3-chlorethyl)-4- methyl-2-oxo-2-H-l-benzopyran-7-yl] carbamate and 14.6 g (0.09 mol) of l-phenylpiperazine were dissolved in 100 ml of chlorobenzene and boiled for 10 hours. After cooling, a precipitate separated out. 150 ml of a chloroform/methanol 1:1 mixture were added to the reaction product and the whole filtered while hot. The

residue obtained was recrystallised twice from dimethyl formamide, washed with alcohol and dried under vacuum. 6.3 g of N-{3-[2- (4-phenylpiperazin-l-yl)ethyl]- 4-methyl-2-oxo-2H-l-benzopyran-7-yl}-4-pheny1-lpiperazine carboxamide was obtained with a melting point of 285 to 288C with decomposition.

For C H N 0 calculated: C 71.84%; H 6.76%; N 12.69%; found: C 71.90%; H 6.72%; N 12.54%.

EXAMPLE 2 N-[3-(2-piperidinoethyl)-4-methyl-2oxo-2H-lbenzopyran7-y1]-l-piperidine carboxamide.

In a manner similar to Example 1, 9.27 g (0.03 mol) of N-[3-(2-chlorety1)-4-methyl-2-oxo-2H-l-benzopyran-7-yl]ethyl carbamate and 8 ml of piperidine in 125 ml of chlorobenzene were boiled for 12 hours. The isolated precipitate was taken up in methanol/chloroform, filtered and the filtrate made alkaline with alcoholic potassium hydroxide solution. The solution was concentrated by evaporation and the product recrystallised from dilute alcohol.

Yield:9 g of the theoretical); melting point 256 260C.

For C H N O calculated: C 69.50%; H 7.86%; N 10.57%; found: C 69.64%; H 7.96%; N 10.57%.

EXAMPLE 3 N-l3-(3-morpho1ino-2-hydroxypropyl)-4-methyl-2- oxo-2H-1-benZopyran-7yll-4-morpholine carboxamide.

The product was prepared in a manner similar to Example 2, from 13.6 g (0.04 mol) of N-[3-(3-chloro-2- hydroxypropyl )-4-methyl-2-0xo-2H- l -benzopyran-7- yllethyl carbamate and 12.2 g (0.14 mol) of morpholine in 250 ml. of chlorobenzene by boiling for 18 hours.

Yield:9.3 g 54% of the theoretical); melting point 224-226C (isopropanol/methylethylketone).

For C H N O calculated: C 61.26%; H 6.76%; N 9.75%; found: C 61.16%; H 6.59%; N 9.53%.

' EXAMPLE 4 N-[ 3-( 3-piperidino-2-hydroxypropyl )-4-methyl-2- oxo-2-oxo-2H-l-benzopyran-7-yl]-l-piperidine carboxamide.

The product was prepared from 13.6 g (0.04 mol of N-[3-(3-chloro-2-hydroxypropyl)-4-methyl-2-oxo-2H- l-benzopyran-7-yl]ethyl carbamate and ml. of piperidine by boiling for 10 hours without solvent.

Yield:7.7 g; melting point: 204-205C (isopropanol) For C H N O calculated: C 67.45%; H 7.77%; N 9.82%; found: C 67.48%; H 7.99%; N 9.50%.

If the base is taken up in chloroform and alcoholic hydrochloric acid is added, the colourless hydrochloride, which melts above 226C with decomposition, is formed.

EXAMPLE 5 N-{3-[3-(4-phenylpiperazin-l-yl)-2-hydroxypropyl]- 4-methyl-2-oxo-2H-l-benzopyran-7y1}-4-phenyl-1- piperazine carboxamide.

The product was obtained from 20.3 g (0.06 mol) of N-[3-( 3-chloro-2-hydroxypropyl )-4-methyl-2-oxo-2H- l-benzopyran-7-yl1ethyl carbamate and 40 g (0.025 mol) of l-phenylpiperazine in 50 m1. of chlorobenzene by boiling for 10 hours, filtering off the precipitate formed after cooling and extracting by boiling several times with isopropanol/chloroform.

Yield:l8.2 g 52% f the theoretical); melting point: 23 3-235C (isopropanol/chloroform).

For C H N O calculated: C 70.20%; H 6.76%; N 12.04%; found: C 69.90%; H. 6.65%; N 11.92%.

EXAMPLE 6.

N[ 3-( 2pyrrolidinoethyl )-4-methyl-2-oxo-2H- 1 benzopyran-7-yl1-l-pyrrolidine carboxamide.

The product was obtained from 14.3 g (0.04 mol) of N-[ 3-( 2-chlorethyl )-4-methyl-2-oxo-2H- 1 -benzopyran-7-yllphenyl carbamate and 20 ml of pyrrolidine in 100 ml of chlorobenzene by heating for six hours at 120C and working up by taking up the filtered-off precipitate in chloroform and washing several times with ZN-sodium carbonate solution.

Yield:7.7 g; melting point 237-238C (chloroform). For C ,H N O calculated: C 68.27%; H 7.37%; N 11.37%; found: C 68.20%; H 7.43%; N 11.23%.

EXAMPLE 7 N-[ 3-( Z-perhydroazepinoethyl )-4-methyl-2-oxo-2H 1-benzopyran-7-yl]-1-perhydroazepine carboxamide.

The product was obtained from 7.1 g (0.02 mol) of N-[ 3-( 2-chlorethyl)-4-methyl-2-oxo-2H- 1 -benzopyran-7yl]phenyl carbamate and 10 ml of perhydroazepine in 100 ml of chlorobenzene by heating for 6 hours at 125C and working up according to Example 6.

Yield:3.7 g; meltiing point: 225C (dimethylformamide).

For C H N O calculated: C 70.56%; H 8.29%; N 9.88%; found: C 70.86%; H 8.19%; N 10.01%.

EXAMPLE 8 N-[3-(2-(4-methylpiperazin-l-yl)ethyl)-4-methyl2- oxo-2H-1-benzopyran-7-yl]-4-methyl-l-piperazine carboxamide.

The product was obtained from 14.3 g (0.04 mol) of N-[ 3-( 2-chlorethyl)-4-methyl-2-oxo-2H- l -benzopyran-7-yl1phenyl carbamate and 20 m1 of l-methylpiperazine in 150 ml of chlorobenzene by heating for seven hours at 125C and working up according to Example 6.

Yield: 1 3 g 75% of the theoretical); melting point: 261C (dimethylformamide).

For C H N O calculated: C 64.61%; H 7.78%; N 16.38%; found: C 64.42%; H 7.64%; N 16.29%.

EXAMPLE 9 EXAMPLE 10 N-[ 3-( Z-piperidinoethyl)-4,8-dimethyl-2-oxo-2H-1- benzopyran-7-yl1-l-piperidine carboxamide.

The product was obtained from 10 g (0.027 mol) of N-[3-(2-chlorethyl)-4,8-dimethyl-2-oxo2H-l-benzopyran-7-yllphenyl carbamate and 17.3 g (0.2 mol) of piperidine in ml of chlorobenzene, in a similar manner to the method of Example 9.

Yield: 5.7 g 51% of the theoretical); melting point: 244-245C (ethylene chloride/ethyl acetate) calculated: C 70.06%; H 8.08%; N 10.21% found: C 69.65%; H 7.98%; N 10.41%.

EXAMPLE 1 1 N-[ 3-( 2-perhydroazepinoethyl )-4,8-dimethyl-2 -oxo.-

2H-1-benzopyran7-yl]1-perhydroazepine carboxam- 1 ide. I

The product was obtained from 22.3 g (0.06 mol) of. N-[3-(2-chlorethyl)-4,8-dimethyl-2 oxo-2H-l-benzopyran-7yl]phenyl carbamate and 44.6 g (0.45 mol) of perhydroazepine in ml of chlorobenzene, by a method similar to that of Example 9.

Yield: 6 g; melting point: -l76C (dimethylformamide/isopropyl ether).

calculated: C 71.04%; H 8.48%; N 9.56%; found: C 71.16%; H 8.26%; N 9.70%.

EXAMPLE l2 N-[3-(2-pyrrolidinoethyl)-4,8-dimethyl-2-oxo-2H-1- benzopyran-7-yl]-l-pyrrolidine carboxamide.

The product was obtained from 22.3 g (0.06 mol) of N-[ 3-( 2-chlorethyl)-4,8-dimethyl-2-oxo-2H- 1 -benzopyran-7-yl1phenyl carbamate and 32 g (0.45 mol) of pyrrolidine in 150 ml of chlorobenzene, by boiling for 2 /2 hours and working up similarly to Example 9. The compound crystallises with V2 mol of ethylene chloride.

Yield: 13.5 g 59% of the theoretical); melting point: 231232C (ethylene chloride/isopropyl ether calculated: C 63.81%; H 7.22%; N 9.71%; found: C 63.41%; H 7.21%; N 9.90%. 1

EXAMPLE 13 N-[3-(2-(4-phenylpiperazin-l-yl)ethyl)-4,8- dimethyl-2-oxo-2H- l -benzopyran-7-yl]-4-phenyll piperazine carboxamide.

The product was obtained from 3.72 g (0.01 mol) of N-[3-(2-chlorethyl)-4,8-dimethyl-2-oxo-2H-l-benzopyran-7-yl]phenyl carbamate and 12.2 g (0.075 mol) of l-phenylpiperazine in 25 ml of chlorobenzene, by boiling for 1V2 hours and recrystallising the filtered precipitate which is then washed with toluene.

Yield: 2.0 g; melting point: 246 247C (dimethylformamide) calculated: C 72.23%; H 6.95%; N 12.37%; found: C

EXAMPLE 14 N-{3-[2-[4-(2-hydroxyethyl)piperazin-1-y1]ethyl]- 4,8-dimethyl-2-oxo-2H-1-benzopyran-7-yll-4-(2- hydroxyethyl)- 1 -piperazine carboxamide.

The product was obtained from 3.72 g (0.01 mol) of N-[3-(2-chlorethy1)-4,8-dimethyl-2-oxo-2H-l-benzopyran-7-yl1phenyl carbamate and 9.75 g (0.075 mol) ot' l-(Z-hydroxyethyl) piperazine in 25 ml of chlorobenzene by boiling for 1% hours, taking up the lower phase which forms on cooling in chloroform and purifying on silica gel. Yield: 1.25 g; melting point: l81-182C (chloroform/ethyl acetate). For C H N O calculated: C 62.25%;1-1 7.84%; N 13.96%; found: C 61.64%; H 7.76%; N 13.68%.

EXAMPLE l5 l-[3-( Z-diethylaminoethyl)-4-methyl-2-oxo-2H- l benzopyran-7-y1]-3,3-diethyl urea.

The product was obtained from 32.1 g (0.09 mol) of N-[3(2-chlorethyl)-4-methyl-2-oxo-2H-1-benzopy ran-7-yl]phenyl carbamate and 60 ml of diethylamine by boiling for 16 hours in 150 ml of nitrobenzene in an autoclave, taking up the filtered off precipitate in 2N- hydrochloric acid, washing the solution with ether, making it alkaline with 2N-potassium carbonate solution, taking up the base in chloroform and purifying on silica gel. Yield: 14.5 g; melting point: 190l9lC (isopropanol).

calculated: C 67.53%; H 8.37%; N 11.25%; found: C 67.94%; H 8.25%; N 11.43%.

The hydrochloride was precipitated from a chloroform solution by introduction of hydrogen chloride at 0C.

Melting point: 223C. For C21H31N3O3 Calculated: C 61.50%; H 7.87%; N 10.25%; Cl 8.65%; found: C 61.45%; H 7.89%; N 10.46%; Cl 8.59%.

EXAMPLE 16 l-{3-[2-(N-cyclohexyl-N-methylamino)ethy1]-4- methyl-2-oxo-2H- l -benzopyran-7-yl}-3-cyclohexyl-3- methyl urea.

The product was obtained from 3.6 g (0.01 mol) of N-[3-(2-chlorethyl)-4-methyl-2-oxo-2H-l-benzopyran-7-yl]phenyl carbamate and 20 ml of N-cyclohexyl- N-methylamine in 25 ml of chlorobenzene by boiling for 8 hours and purifying on silica gel.

Yield: 2.5 g 55% of the theoretical); melting point: 211C (acetone) with decomposition.

Calculated: C 71.49%; H 8.67%; N 9.26%; found: C

EXAMPLE l7 l-{3-[2-(Ncyclohexyl-N-methylamino)ethyl]-4,8- dimethyl-2-oxo-2H-1-benzopyran-7-yl}-3-cyclohexyl- 3-methyl urea.

The product was obtained from 22.3 g (0.06 mol) of N-[3-(2-chlorethyl)-4,8-dimethyl-2-oxo-2H-l-benzopyran-7-yl]pheny1 carbamate and 51 g (0.45 mol) of N-cyclohexyl-N-methylamine in 150 ml of chlorobenzene, distilling off the excess amine and purifying the residue on silica gel.

Yield: 10 g; melting point: 152153C (acetone- /ethyl acetate).

calculated: C 71.91%; H 8.84%; N 8.99%; found: C

EXAMPLE l8 1-[ 3-( 2-morpho1inoethyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl]-3,3-diethyl urea.

8.0 g (0.02 mol) of N-.[3-(2-morpholinoethyl)-4- methyl-2-oxo-2H-l-benzopyran-7-yl]-4-morpholine carboxamide were dissolved in 100 ml of a mixture of chlorobenzene and nit'robenzene (1:1), 50 ml of diethylamine were added thereto and the mixture boiled for 8 hours under reflux. After concentrating the volume to half, cooling and filtering-off, the precipitate was washed with carbon tetrachloride and ether. The yield of analytically pure l-[3-(2-morpholinoethyl)- 4-methyl-2-oxo-2H- l -benzopyran-7-yl]-3 ,3-diethyl urea was 6.6 g 85% of the theoretical). Melting point: 219220C. For C21H29N3O4 calculated: C 65.09%; -H 7.54%; N 10.85%; found: C 65.17%; H 7.36%; N 10.76%.

Using the method described in Example 18, the following compounds were prepared:

EXAMPLE l9 1-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]3-tert.butyl urea.

From 8.0 g (0.02 mol) of N-[3-(2-morpholinoethyl)- 4-methyl-2-oxo-2H- l -benzopyran-7-yl]-4-morpho1ine carboxamide and ml of tertiary butylamine.

Yield: 6.2 g of the theoretical); melting point: 300C with decomposition.

calculated: C 65.09%; H 7.54%; N 10.85%; found: C

EXAMPLE 2O 1-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-l benzopyran-7-yl1-3,3-bis(2-hydroxyethyl)urea.

From 8.0 g (0.02 mol) of N-[3-(2-morpholinoethyl)- 4-methyl-2-oxo-2H- 1 -benzopyran-7-yl -4-morpholine carboxamide and 20 m1 of bis-(2-hydroxyethy1)amine in chlorobenzene for 3 hours at C. Yield: 5.45 g 66% of the theoretical) melting point: 187C with decomposition.

calculated: C 60.13%; H 6.97%; N 10.02%; found: C

EXAMPLE 21 I-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-l benzopyran-7-yl]-3-phenyl urea.

From 8.0 g (0.02 mol) of N-[3-(2-morpholinoethyl)- 4-methyl-2-oxo-2H- l -benzopyran-7-yl]-4-morpholine carboxamide and 50 ml of aniline in nitrobenzene for 6 hours at 130C (bath temperature).

Yield: 6.7 g 83% of the theoretical); melting point: 290C with decomposition.

calculated: C 67.79%; H 6.18%; N 10.31%; found: C

EXAMPLE 22 N-[ 3-(2-morpholinoethyl)-4-methy1-2-oxo-2H- l benzopyran-7-yll-4-(2-hydroxyethyl)-1-piperazine carboxamide.

From 3.0 g (0.0075 mol) of N-[3-(2-morpholinoethyl)- 4-methyl-2-oxo-2H-1-benzopyran-7-yl]-4.-morpholinc carboxamide and 30 ml of l-(2-hydroxyethyl)piperazine in chlorobenzene/nitrobenzene for 4 hours at C (bath temperature).

Yield: 1.8 g 54% of the theoretical); melting point: 210C with decomposition.

For C23H32N405 calculated: C 62.14%; H 7.25%; N 12.61%; found: C 61.88%; H 7.21%; N 12.71%.

EXAMPLE 23 N-[ 34 2-morpholinoethyl )-4-methyl-2-0XO-2H- l benzopyran-7-yl]-l-piperidine carboxamide.

From 8.0 g (0.02 mol) of N-[3-(2-morpholinoethy1)- 4-methyl-2-oxo-2l-l-1-benzopyran-7-yll-4-morpholine carboxamide and 50 ml of piperidine for 6 hours at 120C.

Yield: 7.5 g 95% of the theoretical); melting point: 256C with decomposition. For CgzHggNgOq calculated: C 66.14%; H 7.32%; N 10.52%; found: C

EXAMPLE 24 l-[ 3-(2-morpholinoethyl)-4methyl-2-oxo-2H- 1 benzopyranJ-yl]-3-cyclohexyl urea.

From 8.0 g (0.02 mol) of N-[3-(2-morpholinoethyl)- 4-methyl-2-oxo-2H- l -benzopyran-7-yl]-4-morpholine carboxamide and 50 ml of cyclohexylamine for 5 hours at 120C.

Yield: 6.5 g 79% of the theoretical); melting point: 275C with decomposition. For C I-1 N calculated: C 66.80%; H 7.56%; N 10.16%; found: C

EXAMPLE 25 1-[ 3-( 2-diethylaminoethyl)-4-methyl-2-oxo-2l-l-l benzopyran-7-yl]-3-phenyl urea.

From 8.0 g (0.021 mol) of 1-[3-(2-diethylaminoethyl)- 4-methyl'2-oxo-2l-Ll-benzopyran-7-yl]-3,3-diethyl urea and 50 ml of aniline. Yield: 6.0 g 72% of the theoretical); melting point: 265C with decomposition. For C H N O calculated: C 70.20%; H 6.92%; N 10.68%; found: C 70.05%; H 6.68%; N 10.66%.

EXAMPLE 26 N- 3-( 2-morpholinoethyl)-4,8-dimethyl-2-oXo-2H- l benzopyran-7yl]-4-( 2-hydroxyethyl) l -piperazine carboxamide.

From 16.6 g (0.04 mol) of N-[3-(2-morpholinoethyl)- 4.8-dimethyl-2-oxo-2H- l -benzopyran-7-yl]-4- morpholine carboxamide and 150 ml of l-(2-hydroxyethyl)piperazine in 150 ml of chloroben- :zene. Yield: 6 g; melting point: 186l87C. For C I-1 N 0 calculated: C 62.86%; H 7.47%; N 12.22%; found: C 63.39%; H 7.29%; N 12.26%.

EXAMPLE 27 1-[3-(2-morpholinoethyl)-4-methyl2-oxo-2H-l benzopyran-7-yl]-urea.

5.56 g (0.0135 mol) of N-[3-(2-morpholinoethyl)-4- methyl2-oxo-2H-l-benzopyran-7-yl]phenyl carbamate are dissolved in 120 ml of dimethylformamide and 50 ml of cold ammoniacal ethanol are added. After stirring for 6 hours, the mixture is suction-filtered, the precipitate is washed with acetone and dried under vacuum. 2.9 g 65% of the theoretical) of 1-[3-(2- morpholinoethyl)-4-methyl- Z-oXo-ZH-1-benzopyran-7-yl]urea with a melting point higher than 300C with decomposition, are obtained. F01 C17H21N304 calculated: C 61.62%; H 6.39%; N 12.68%; found: C 61.57%; H 6.54%; N 12.38%;

EXAMPLE 28 N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-lbenzopyran-7-yl]-2-methyl-4-morpholine carboxamide.

5.56 g (0.0136 mol) of N-[3-(2-morpholinoethyl)-4- methyl-Z-oxo-ZH-l-benzopyran-7-yl]phenyl carbamate are dissolved in 120 ml of dimethylformamide and 20 ml of 2-methylmorpholine are added. After stirring for 6 hours, the colourless precipitate is filtered with suction and washed wish acetone. 3.15 g 55% of the theoretical) of N-[ 3-( 2-morpholinoethyl)-4-methy1-2-.

oxo-2H-1-benzopyran-7-y1]-2-methyl-4-morpho1ine carboxamide with a melting point of 256257C with decomposition, are obtained. For C H N O calculated: C 63.59%; H 7.04%; N 10.1 1%; found: C 63.84%; H 6.73%; N 10.12%.

The following compounds were prepared in a similar manner to that of Example 28:

EXAMPLE 29 1'[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]3,3-diisopropyl urea.

The product was obtained from 3.0 g (0.0067 mol) of N-[ 3-( 2-morpholinoethyl )-4-methyl-2-oxo-2H- l benzopyran-7-yl]phenyl carbamate and 40 ml of diisopropylamine by standing for 24 hours and pouring into water. Yield: 2.3 g 85% of the theoretical); melting point: 215C with decomposition.

F01 C23H33N3O4 calculated: C 66.48%; H 8.01%; N 10.11%; found: C 66.65%; H 8.00%; N 10.48%.

EXAMPLE 30 1-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-3-tert.-butyl-3-(2- hydroxyethyl)urea.

The product was obtained from 6.5 g (0.015 mol) of N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-l-benzopyran-7yl] phenyl carbamate and 15 ml of 2-tert.- butylaminoethanol.

Yield: 4.0 g 63% of the theoretical); melting point: l176C with decomposition. For C23H33N3O5 calculated: C 64.01%; H 7.71%; N 9.74%; found: C

EXAMPLE 31 EXAMPLE 32 l-[ 3-( 2-morpholinoethyl)-4,8-dimethyl-2-oXo-2H- l benZopyran-7-yl]-3,3-bis(2-hydroxyethyl)urea.

16.6 g (0.04 mol) of N-[3-(2-morpholinoethyl)-4,8- dimethyl-2oxo-2H-1-benzopyran-7-yl]-4-morpholine carboxamide are dissolved in 100 ml of chlorobenzene, 80 ml of bis(2-hydroxyethyl)amine are added and the mixture stirred for 2 hours at 130C. The precipitate obtained and isolated on cooling is stirred into 500 ml of water, filtered with suction, dried and purified on silica gel. There are obtained 1 1.4 g 66% of the theoretical) of 1-[3-(2-morpholinoethyl)- 4,8-dimethyl-2-0xo-2l-ll-benZopyran-7-yl]- 3,3-bis(2-hydroxyethyl)urea with a melting point of 20 l202C.

calculated: C 60.95%; H 7.21%; N 9.69%; found: C

EXAMPLE 33 N-[3-(2-m0rpholinoethyl-4-methyl-2-oxo-2H-l-benzopyran-7-yl]-N-methyl-4-morpholine carboxamide.

6 g (0.02 mol) of 7-methylamino-3-(2-morpholinoethyl)- 4-methyl-2-oxo-2l-l-l-benzopyran are dissolved in 150 ml of chloroform and 0.04 mol of phosgene in 40 ml of toluene are added dropwise. After standing for 12 hours, the excess solvent and phosgene are distilled off and the resultant N-[3-(2-morpholinoethyl)-4- methyl-2-oxo-2H-l-benzopyran-7-yl]-N-methyl chloroformic acid amide is heated without isolation with 120 g (1.38 mol) of morpholine for 2 hours to 40C. After evaporating the excess morpholine, the residue is taken up in chloroform, extracted by shaking with potassium-hydrogen carbonate and the organic phase is freed from the chloroform. The oil which is obtained is crystallised by adding cyclohexane. 7.1 g 85.7% of the theoretical) of N-[3-(2-morpholinoethyl)-4- methyl-Z-oxo-Zl-l- 1 -benzopyran- 7-yll-N-methyl-4-morpholine carboxamide having the melting point of l 141 16C are obtained.

FOr C22H29N305 calculated: C 63.59%; H 7.03%; N 10.11%;

found: C 63.69%; H 7.10%; N 10.16%.

The following compounds can be prepared in a manner similar to that of Example 33:

N-[ 3-( 2-morpholinoethyl)-4-methyl-2-oxo-2H-1 benzopyran- 7-yl]-N-methyl-2-methyl-4-morpholine carboxamide; melting point: 142 to 145C.

N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-lbenzopyran-7-yl]-N-methyl-lperhydroazepine carboxamide; melting point: 98-l01C.

l-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-lbenzopyran-7-yl]-l-methyl-3,3-diethyl urea; melting point: 1l3115C.

N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yll-N-methyl-Z-methyl-l-aziridine carboxamide; melting point 105-107C.

l-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-lbenzopyran-7-yl]-l,3-dimethyl-3-cyclohexyl urea;

l 13-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran- 7-yl]-l-methyl-3,3-bis(Z-hydroxyethyl) urea;

1-[3-(2-morpholinoethy1)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-l-methyl-3,3'diisopropyl urea;

l-[ 3-( Z-morpholinoethyl)-4-methyl-2-oxo-2H- l ben2opyran-7-yl] l -methy1-3 ,3-diisobutyl melting point: 136-138C.

l 3-(2-morpholinoethyl)4-methyl-2-oxo2H- 1- benz0pyran-7-yl1-l-methyl3-tert.butyl urea; melting point: l33-135C.

N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-lbenzopyran-7-yl]-N-methyl-4-methyl-l-piperazine carboxamide; melting point: 1 l6l 19C.

N-[3-(2-morpho1inoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-N-ethyl-4methyll -piperidine carboxamide; melting point: l53156C.

N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-N-ethyl-4-morpholine carboxamide; melting point l2l123C.

N[ 3-( 2-morpholinoethyl)-4-methyl-2-oxo-2H- 1 benzopyran-7-yl -N-ethyl-4 methyll -piperazine carboxamide; melting point: l60-161C.

1 -[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-1-ethyl-3,3-bis(2-hydroxyethyl) urea;

1-[ 3-(2-morpholinoethyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl]-l-ethyl-3,3-diisopropyl urea;

1-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]- 1 -ethyl-3-cyclohexyl urea;

N-[3-(2-morpholinoethyl)-4-phenyl-2-oxo-2H-1- benzopyran-7-yl]'4-morpholine carboxamide (melting point: 244-245C), is formed by heating N-[ 3-( 2-chlorethyl )-4-phenyl-2-oxo-2H- l-benzopyran-7-yl1phenyl carbamate in excess morpholine and working up as indicated above. From this compound, by the action of an excess of corresponding amines, as described, the following compounds are produced.

N-[3-(2-morpholinoethyl)-4-phenyl-2-oxo-2H-1- urea;

benzopyran-7-yl]-l-perhydroazepine carboxamide; l-[3-(2-morpholinoethyl)4-phenyl2-oxo-2H-1-benzopyran- 7-yl]-3'( 1 ,1-dimethyl-2-hydroxyethyl)urea;

1-[3-(2-morpholinoethy1)-4-phenyl-2-oxo-2l-l-1-benzopyran-7-yl1-3,3-bis(2-hydroxypropyl)urea.

N-[ 3-( 2-morpholinopropyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl]-4-morpholine carboxamide;

from N-[3-(2-Chloropropyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl] phenyl carbamate by reaction with morpholine.

By reacting the compound obtained above with amines, the following compounds can be prepared:

l[3-(2-morpholinopropyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl]-3,3-bis(2-hydroxyethyl)urea;

l-[ 3-( 2-morpholinopropyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl]-3-cyclohexy1urea;

N-[ 3-( 2-morpholinopropyl)-4'methyl-2-oxo-2H- 1 benzopyran-7-yl]-3-methyl-l-piperidine carboxamide;

N-[3-(2-morpholinopropyl)-4-methyl-2-oxo-2H-lbenZopyran-7-yl]-2-methyl-l-aziridine carboxamide.

N-[3-(2-morpholinobutyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-4-morpholine carboxamide, with the melting point 238239C, from N-[3-(2- chlorbutyl)-4-methyl-2-oxo-2H-1-benzopyran-7- yl]phenyl carbamate and morpholine. By reamidation of the above compound, the following substances are obtainable:

N-[3-(2-morpholinobutyl)-4-methyl2-oxo-2H-lbenzopyranJ-yl]-2-methyl-l-piperidine carboxamide; I

1[3-( 2morpholinobutyl)-4-methyl-2-oxo-2H- l ben2opyran-7-yl]-3,3-diethyl urea;

1 3-(2-morpholinobutyl)-4-methyl-2-oxo-21-l-1- benzopyran-7-yl]-3-methyl-3-(2-hydroxyethyl) urea;

1-[ 3-( 2-morpholinobutyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl -3-cyclohexyl-3-( 2- hydroxyethyl)urea;

In similar manner to the compounds described above, it is possible to prepare:

N-[ 3-(2-morpholinoethyl)-4,6-dimethyl-2-oxo-2H-1- benzopyran-7-yll-4-morpholine carboxamide; melting point 192-193C;

N-[3-(2-morpholinoethyl)-4,6-dimethyl-2-oxo-2l-l-1- benzopyran-7-yl1- l -perhydroazepine carboxamide; melting point 175l76C;

N-[3-(Z-morpholinoethyl)-4,6-dimethyl-2-oxo-2l-l-1- benzopyran-7-yl]-4-methyl-1-piperazine carboxamide;

1-[ 3-(2-rnorpholinoethyl)-4,6-dimethyl-2-oxo-2H-1- benzopyran-7-yl]-3-cyclohexyl-3-(2- hydroxyethyl)urea; melting point l98-199C;

l-[ 3-(2-morpholinoethyl-4,6-dimethyl-2-oxo-2l-l-1- benzopyran-7-yl1-3,3-diisobutylurea; melting point l91l93C;

N-[ 3-( 2-morpholinoethyl)-6-chloro-4-methyl-2-oxo- 2H-1-benzopyran-7-yl]-4-morpholine carboxamide;

1-[ 3-( 2'morpholinoethyl)-6-chloro-4-methyl-2-oxo- 2H- 1 -benzopyran-7yl]-3,3-diethyl carboxamide; l-[ 3-( 2-morpholinoethyl) 6-chloro-4-methyl-2-oxo- 21-1-1-benzopyran-7-yl]-3-(4-methylcyclohexyl- )urea;

1-[ 3-( Z-morpholinoethyl)-6-chloro-4-methyl-2-ox0- 2H-1-benzopyran-7-y1]-3,3-diisobutyl urea;

N-[ 3-( 2-morpholinoethy1)-6-chloro-4-methy1-2-oxo- 2H-1-benzopyran-7-yl]-3-methy1-l-piperidine carboxamide;

1-[ 3-( 2-morpholinoethyl)-6-chloro-4-methyl-2-oxo- 2H-1-benzopyran-7-yl]-3,3-bis(2- hydroxypropyl)urea;

1-[ 3-( 2-Anilinoethyl )-4-methyl-2-oxo-2H- l -benzopyran-7-yl]3-phenylurea;

1-[3-(2-morpholinoethyl)-4-methy1-2-oxo-2H-1- benzopyran-7-yl]-3-(4-methylphenyl)urea; melting point 295C (with decomposition);

1-[3-(2-morpholinoethyl-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-3-(4-chlorophenyl)urea; melting point 290C (with decomposition);

l-[ 3-( Z-morpholinoethyl )-4-methyl-2-oxo-2H- l benzopyran-7-yl]-3-( 3-trifluoromethylphenyl- )urea;

N-[ 3-( 2-morpholinoethyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl]-2-methyl-l-aziridine carboxamide; melting point 200C (with decomposition);

1-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-3-(4-hydroxyphenyl)urea;

l 3-(2-morpholinoethyl)-4-methyl-2-oxo-2l-l-1- benzopyran7-yl]-3-(4-methoxyphenyl)urea; melting point 280C with decomposition;

l-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-3,3-dicyclohexylurea; melting point 235C.

N-[3-(2-morpholinoethyl)-2-oxo-2H-1-benzopyran- 7-yll-4-morpholine carboxamide with the melting point 232C, and the compounds listed below, can be prepared from 7-amino-3-(2-bromethyl)2-oxo- 2H-l-benzopyran by methods similar to those described in the preceding Examples:

N- 3-( 2 morpholinoethyl )-2-oxo-2H- 1 -benzopyran- 7-yl]-2-methyl-1-piperidine carboxamide;

l-[3-(Z-morpholinoethyl)-2-oxo-2H-1-benzopyran- 7-yl]-3,3-diethylurea; melting point: 193-194C.

l-[3-(2-morpholinoethyl)-2-oxo-2H-1-benzopyran- 7-y1]-3-methyl-3-cyclohexyl urea;

N-[ 3-(2-morpholinoethyl)-2-oxo-2l-l-1-benzopyran- 7-yl]-2-methyl-1-aziridine carboxamide;

l-[ 3-( 2-morpholinoethyl )-2-oxo-2H- 1 -benzopyran- 7-yl]-3,3-diisobutylurea;

N-[3-(2-morpholinoethyl)-2-oxo-2l-l-1-benzopyran- 7-yl]-4-methyl- 1 -piperazine carboxamide;

N-[ 3-( 2-morpho1inoethyl)-2-oxo-2H- 1 -benzopyran- 7-y1]- 1 -perhydroazepine carboxamide;

1-[3-(Z-diisobutylaminoethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl]-4-morpholine carboxamide; melting point 251C.

EXAMPLE 34 N-[ 3-( 2-morpholinoethyl-4-methyl-2-oxo-2l-lbenzopyran-7-yl]-4-morpholine carboxamide.

a. N-[3-(2-chlorethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl1phenyl carbamate.

22.9 g (0.1 mol) of N-(3-hydroxyphenyl)phenyl carbamate and 12.8 g (0.1 mol) of Z-acetyl-ybutyrolactone are dissolved in a mixture of 160 l ml of ethanol and 40 ml of dimethylformamide. Hydrochloric acid gas is introduced into the cooling solution to saturation point and the reaction mixture is then kept for 24 hours at room temperature. Thereafter, the solvent is distilled off, the residue is stirred into 600 ml of water, the crystalline precipitate is separated out, washed with water and dried. The product obtained by recrystallisation from isopropanol is dissolved in 800 ml of ethylene chloride, 12 g (0.1 mol) of thionyl chloride areadded dropwise under heat and boiling takes place for 8 hours under reflux. On cooling, a crystalline precipitate is obtained, and after crystallisation from ethylene chloride, this yields 26.9 g of the theoretical) of N- [3-(2-chlorethyl)-4-methyl-2-oxo-2H-1- benzopyran-7-yl1phenyl carbamate. The compound melts at 220 to 221C.

For C19Hl6ClNO4 calculated: C 63.9%; H 4.52%; Cl 9.92%; N 3.84%; found; C 63.92%; H 4.41%; Cl 10.10%; N 3.84%.

b. N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2l-l-1- benzopyran-7-yl]-4-morpho1ine carboxamid e hydrochloride 26.8 g (0.075 mol) of N-[3-(2-chlorethyl)-4- methyl-2-oxo-2H-1-benzopyran-7-yl]pheny1 carbamate and g (1.15 mol) of morpholine are boiled under reflux in 800 ml of chlorobenzene for 10 hours. On cooling, a crystalline precipitate is obtained, which is filtered with suction and washed with benzene. Thereafter, the precipitate is dissolved in chloroform, the solution is washed with water, and dried over sodium sulphate. Anhydrous hydrochloric acid gas is then introduced into this solution while cooling, the forming precipitate is suction-filtered and washed with chloroform. After recrystallisation from methanol/ water, there are obtained 15 g (46% of the theoretical) of N-I3-(2-morpholinoethyl)-4-methy1- 2-oxo-2H-1-benzopyran-7-yl]-4-morpholine carboxamide hydrochloride, which melts at 291 to 294C with decomposition.

Calculated: C 57.65%; H 6.45%; N 9.60%; Cl 8.1 1%; found: C 57.85%; H 6.34%; N 9.71%; Cl 8.00%.

c. N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2l-l-lbenzopyranJ-yl]-4-morpholine carboxamide.

The hydrochloride as previously described is dissolved in water and 2N sodium hydroxide solution is added. The liberated base is extracted by shaking with chloroform, washed with water and the solution is dried. After evaporating the solvent and recrystallising from isopropanol/chloroform, N-[3-(2- morpholinoethyl)-4-methyl-2-oxo-2H- l -benzopyran-7- yl]-4-morpholine carboxamide with a melting point of 270 to 271C (with decomposition) is obtained.

Calculated: C 62.82%; H 6.78%; N 10.47%; Found:

C 63.16%; H 6.83%; N 10.42%.

EXAMPLE 35 N-[ 3-(2-morpholinoethyl)-4-methy1-2-oxo-2H-l benzopyran-7-yl]-4-morpholine carboxamide.

a. N-[3-(2-chlorethyl)-4-methyl-2-oxo-2H-lbenzopyran-7-yl1ethyl carbamate.

32.6 g (0.18 mol) of N-(3-hydroxyphenyl)ethyl carbamate and 23.1 g (0.18 mol) of 2-acetyl-'ybutyrolactone are dissolved in 500 ml of absolute methanol, saturated at to 30C with dry hydrochloric acid gas and kept for 24 hours at room temperature. A crystalline precipitate is formed, which is suction-filtered and suspended in 800 ml of ethylene chloride. 21.4 g (0.18 mol) of thionyl chloride are then added dropwise with heating and the solution is boiled for 1 hour. After cooling and suction filtering the formed precipitate, followed by recrystallisation from ethylene chloride, there are obtained 25 g (45% of the theoretical) of N-[3-(2-chlorethyl)-4- methyl-2-oxo-2l-l-l-benzopyran-7-yl]-ethyl carbamate with a melting point of 227 to 228C.

Calculated: C 58.10%; H 5.21%; C1 11.45%; N 4.52%; Found: C 58.29%; H 5.19%; Cl 11.26%; N 4.28%.

b. N-[3-(2-morpholinoethyl)-4-methyl-2-oxo-2l-l-lbenzopyran-7-y1]-4-morpholine carboxamide.

9.3 g (0.03 mol) of N-[3-(2-chlorethyl)-4-methyl- 2-oxo-2H-l-benzopyran-7-yl1ethyl carbamate and 9 g (0.103 mol) of morpholine are boiled under reflux in the absence of moisture for 20 hours in 125 ml of chlorobenzene. The solvent is then evaporated, the residue dissolved in chloroform, the solution washed and dried and the organic phase concentrated by evaporation. By repeated recrystallisation of the residue from isopropanol/chloroform, there are obtained 7.8 g (65% of the theoretical) of pure N-[3-(2- morpholinoethyl)-4-methyl-2-oxo-2H-lbenzopyran-7-yl]-4-morpholine carboxamide with a melting point of 270 to 271C. The substance is identical with that described in Example 34.

EXAMPLE 36 Specific formulations of various conventional forms ready for use are set out below.

In these examples, the compound N-[3-(2- morpholinoethyl )-4-methyl-2-oxo-2H- l -benzopyran-7- yll-4-morpholine carboxamide hydrochloride, hereinafter referred to as A, is used as active principle.

Tablets a. 150.0 mg of A 163.0 mg of lactose 1 10.0 mg of maize starch 13.5 mg of PVP 12.0 mg of talcum 1.5 mg of magnesium stearate 450.0 mg All substances are mixed. The mixture is initially pressed into briquette form. These briquettes are crushed the granulated material is comminuted to a uniform grain size of about 1 mm and compressed to form tablets with a weight of 450 mg and a diameter of l 1 mm.

Dragees b. 150.0 mg of A 100.0 mg of lactose 50.0 mg of maize starch 10.0 mg of PVP 9.0 mg of talcum 1.0 mg of magnesium stearate 320.0 mg

Preparation of a granulated material as under a). Compression into dragee cores with a weight of 320 mg and a diameter of 10 mm.

The cores can be coated in known manner with sugar solutions or lacquered with lacquer solutions.

0. Suppositories 300 mg of A 1700 mg of hard fat DAB 7 The extremely finely ground A is well suspended in the molten base at a temperature not above 45C and homogenised. 'The homogeneous mass is poured into moulds.

d. For using the compounds according to the invention in a form which can be injected, the injection solution is preferably prepared immediately before use. For this purpose, it is advantageous to use a dry ampoule, in which the active principle or because of the better solubility in water the mixture of the active principle with a physiologically acceptable acid or the salt of the active principle with an acid is contained.

Substances which have proved particularly suitable are the mono salts of polybasic acids, such as tartaric acid, citric acid, adipic acid; obviously also monobasic acids, such as lactic acid, can also be used.

As a single dose of the active material, amounts between 25 and mg are to be considered. The active material is dissolved immediately before the injection in 2 ml of water per injection.

d1. Example for the preparation of a dry ampoule with a mixture of N-[3-(2-morpholinoethyl)-4- .methyl-4-oxo-2H- l-benzopyran-7-yl1-4- morpholine carboxamide (hereinafter designated as B) and tartaric acid:

500 g of B are intimately mixed with 186.8 g of tartaric acid. 69 mg of this mixture are introduced under aseptic conditions into ampoules having a normal capacity of 5 ml, so that the indicated quantity is sufficient for filling 10,000 ampoules.

d2. Example of the preparation of a dry ampoule of a salt of B and tartaric acid:

500 g of B are heated in 5 litres of chloroform and 1 litre of methanol is added. A solution of 186 g of tartaric aicd in 1 litre of methanol is then also added. The forming solution is concentrated by evaporation under vacuum to 5 litres. Each 0.5 ml of this solution is introduced with a suitable device into ampoules and subjected to freezedrying, the salt forming in amorphous form, which contains per ampoule 50 mg of B as hydrogen tartrate. Thereafter, the ampoules are sealed. The quantities used are sufficient for the preparation of 10,000 dry ampoules.

What is claimed is:

l. A compound of the formula (I) *{s f (1) R6 N l: N 0

l f1 1, U N R2 wherein R R R and R are hydrogen, or straightchain or branched-chain alkyl or mono hydroxyalkyl of up to 4 carbon atoms, cyclohexyl phenyl or phenyl substituted with one of chloro, hydroxy, lower alkyl or alkoxy of l to 3 carbon atoms, or trifluoromethyl; at least one of the radical pairs R and R and R and R when taken together with the adjacent nitrogen atom, represent al kyleneimino of from 2 to 6 ring carbon atoms or said alkyleneimino substituted by methyl; or morpholino, methylmorpholino, piperazino, 4phenylpiperazine, or 4-alkyl or mono hydroxyalkyl piperazino wherein the alkyl moiety has up to 5 carbon atoms;

R, is hydrogen, lower alkyl of up to 3 carbon atoms;

R is hydrogen, lower alkyl of up to 3 carbon atoms,

or phenyl;

Z is chloro or lower alkyl of up to 3 carbon atoms;

n represents a number from O to 2, and

U is straight-chain or branched-chain lower alkylene,

or monohydroxyalkylene, of from 2 to 5 carbon atoms;

or the pharmacologically acceptable salts thereof.

2. A compound as claimed in claim 1 in which at least one of R,, R R and R are alkyl or hydroxyalkyl.

3. A compound as claimed in claim 1 in which at least one of R R R and R is cyclohexyl, phenyl or phenyl substituted with one of chloro, hydroxy, lower alkyl or alkoxy of l to 3 carbon atoms, or trifluoromethyl.

4. A compound as claimed in claim 1 in which at least one of the radical pairs R and R and R and R is morpholino.

S. A compound as claimed in claim 1 in which at least one of the radical pairs R and R and R and R is alkyleneimino of from 2 to 6 ring carbon atoms.

6. A compound as claimed in claim-1 in which at least one of the radical pairs R and R and R and R is piperazino.

7. A compound as claimed in claim 1 wherein at least one of the radical pairs R and R and R and R is 4- phenyl-, 4-alkylor 4-hydroxyalkylpiperazino of up to 5 carbon atoms in the alkyl moiety.

8. A compound as claimed in claim 1 wherein one of the radical pairs R and R and R and R is morpholino and the other is alkyleneimino of from 2 to 6 ring carbon atoms or piperazino, 4-phenylpiperazino, 4 alkylpiperazino or 4-hydroxyalkylpiperazino.

9. A compound as claimed in claim 1 wherein one of the radical pairs R and R and R and R is morpholino and the other radicals are hydrogen, alkyl or hydroxyalkyl.

10. Compound as claimed in claim 1, designated N- l 3-[2-( 4-phenylpiperazin-l -yl)ethyl]-4-methyl-2-oxo- 2H- 1 -benzopyran-7-yl }-4-phenyl- 1 -piperazine carboxamide.

11. Compound as claimed in claim 1 designated N- [3-( 2-morpholinoethyl-4-methyl-2-oxo-2l-ll benzopyran-7-yl]-4-morpholine carboxamide.

12. Compound as claimed in claim 1, designated N- 2'piperidinoethyl )-4-methyl-2-oxo-2l-ll benzopyran-7-yl1-l -piperidine carboxamide.

13. Compound as claimed in claim 1, designated N- -(3-morpholino-Z-hydroxypropyl)-4methyl-2-oxo2H- lbenzopyran-7-yl]-4-morpholine carboxamide.

14. Compound as claimed in claim 1, designated N- -(3-piperidino-Z-hydroxypropyl)-4-methyl-2-oxo-2H- l-benzopyran-7-yl1- l -piperidine carboxamide.

15. Compound as claimed in claim 1, designated 3-( 4-phenylpiperazinl -yl)-2-hydroxypropyl]-4- methyl2-oxo-2H- l-benzopyran-7-yl -4-phenyl-l-piperazine carboxamide.

16. Compound as claimed in claim 1 designated l-[3- (2-diethylaminoethyl)-4-methyl-2-oxo-2H- l benzopyran-7-yl]-3,3-diethyl urea.

17. Compound as claimed in claim 1 designated N- T23- -perhydroazepinoethyl)-4-methyl-2-oxo-2l-l-1- benzopyran-7-yl]-l-perhydroazepine carboxamide.

18. Compound as claimed in claim 1 designated N- 2-morpholinoethyl )-4-methyl-2-oxo-2H- l benzopyran-7-yl1- l -piperidine carboxamide.

19. Compound as claimed in claim 1 designated l-[3- (2-morpholinoethyl )-4-methyl-2-oxo-2H- l benzopyran-7-yl]-3,3-diethyl urea.

20. Compound as claimed in claim 1 designated N-[3-(2rmorpholinoethyl)- 4-methyl-2-oxo-2H- l -benzopyran-7-yl -2-methyl- 4-morpholine carboxamide.

" CER'IIMCA'LE] OF' c-onn mcfrle-N .,j a'm: 5." $8 42 Dated ly-2 2 75 1 v r( Karl Heinz Beeker et a1.

1: is ceriified that error appears/in the aboymidentified patent .and that said Letters Patent are hereby corrected as shown below:

T x I 1 Correct: filing date to read July l5, l97l" Column... 3, line 61 "sample" should read --simpl'e-- Column 4, line 33 "intersecting" should read -'--interesting-- "Column 8, line of f Cla A Qua l? i UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5, 97, Dated July 1975 Inventor(s) Karl Heinz Becker et al. Page 2 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column ll, line ll "(p andg)" omitted Column-.11, line 61 I "carbonxamide" should be carbox amide-- Column -12, linetl .'chloretyl" should be -chlorethyl- Column'l7, line 61 "(0.0135 mole)" should be (O.Ol36 mole)-- Column 20, line .45 v "chloroprop yl 'Y should be -'chlorpropylt Column 22, line 20 v "2H'-" should be -2H 1- Colurnn 26,v 1111824, (N-(3" .shouldread T- ,N-L3*- 3-.--

Column 26, line 34 I after "designated" add- N- (3 Column 26, line 43 j "T 23" should be "5-42- Signcd and Sealed this eighteenth Day Of November 1975 [SEAL] Arte-s1:

RUTH C. MASON C. MARSHALL DANN :IIH'AIIHX ()jjm' (nmmissimlcr nl'luu'nls and Tradcmurkx 

1. A COMPOUND OF THE FORMULA (1)
 2. A compound as claimed in claim 1 in which at least one of R1, R2, R5 and R6 are alkyl or hydroxyalkyl.
 3. A compound as claimed in claim 1 in which at least one of R1, R2, R5 and R6 is cyclohexyl, phenyl or phenyl substituted with one of chloro, hydroxy, lower alkyl or alkoxy of 1 to 3 carbon atoms, or trifluoromethyl.
 4. A compound as claimed in claim 1 in which at least one of the radical pairs R1 and R2, and R5 and R6, is morpholino.
 5. A compound as claimed in claim 1 in which at least one of the radical pairs R1 and R2, and R5 and R6, is alkyleneimino of from 2 to 6 ring carbon atoms.
 6. A compound as claimed in claim 1 in which at least one of the radical pairs R1 and R2, and R5 and R6, is piperazino.
 7. A compound as claimed in claim 1 wherein at least one of the radical pairs R1 and R2, and R5 and R6, is 4-phenyl-, 4-alkyl- or 4-hydroxyalkylpiperazino of up to 5 carbon atoms in the alkyl moiety.
 8. A compound as claimed in claim 1 wherein one of the radical pairs R1 and R2, and R5 and R6, is morpholino and the other is alkyleneimino of from 2 to 6 ring carbon atoms or piperazino, 4-phenylpiperazino, 4-alkylpiperazino or 4-hydroxyalkylpiperazino.
 9. A compound as claimed in claim 1 wherein one of the radical pairs R1 and R2, and R5 and R6, is morpholino and the other radicals are hydrogen, alkyl or hydroxyalkyl.
 10. Compound as claimed in claim 1, designated N-(3-(2-(4-phenylpiperazin-1-yl)ethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl) -4-phenyl-1-piperazine carboxamide.
 11. Compound as claimed in claim 1 designated N-(3-(2-morpholinoethyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-4-morpholine carboxamide.
 12. Compound as claimed in claim 1, designated N-(3-(2-piperidinoethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-1-piperidine carboxamide.
 13. Compound as claimed in claim 1, designated N-(3-(3-morpholino-2-hydroxypropyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-4 -morpholine carboxamide.
 14. Compound as claimed in claim 1, designated N-(3-(3-piperidino-2-hydroxypropyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-1 -piperidine carboxamide.
 15. Compound as claimed in claim 1, designated N-(3-(3-(4-phenylpiperazin-1-yl)-2-hydroxypropyl)-4-methyl-2-oxo-2H-1 -benzopyran-7-yl)-4-phenyl-1-Piperazine carboxamide.
 16. Compound as claimed in claim 1 designated 1-(3-(2-diethylaminoethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-3,3-diethyl urea.
 17. Compound as claimed in claim 1 designated N-(3-(2-perhydroazepinoethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-1 -perhydroazepine carboxamide.
 18. Compound as claimed in claim 1 designated N-(3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-1-piperidine carboxamide.
 19. Compound as claimed in claim 1 designated 1-(3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-3,3-diethyl urea.
 20. Compound as claimed in claim 1 designated N-(3-(2-morpholinoethyl)-4-methyl-2-oxo-2H-1-benzopyran-7-yl)-2-methyl-4 -morpholine carboxamide. 